Sitagliptin (compound of formula I) is an oral antihyperglycemic drug used for treatment of diabetes.

The pharmacological activity of Sitagliptin is attributable to (R)-enantiomer and many syntheses have been recently developed to prepare the enantiomerically pure compound (U.S. Pat. No. 6,699,871, U.S. Pat. No. 7,307,164, US20060052382, U.S. Pat. No. 7,468,459, U.S. Pat. No. 7,326,708, U.S. Pat. No. 7,125,873, Drug of the future 2005, 30, 337, Chinese J. Pharm. 2008, 39, 383). Although the synthesis of the heterocyclic fragment containing four nitrogen atoms in 5-/6-membered ring system has been already sufficiently resolved (e.g. J. Med. Chem. 2005, 48, 141 or Drug of the future 2005, 30, 337), there is still a need for a better and more cost efficient synthesis of the second building block, the (R)-β-amino acid of formula IIa.

For the preparation of this (R)-β-amino acid and derivates thereof many different approaches have been published but in all the chiral center has been specifically formed during the synthesis. Originally (R)-enantiomer has been prepared via resolution of a racemate (Chinese Chem. Lett. 2009, 20, 1397, Chinese J. Synth. Chem. 2010, 6, 767 and Org. Biomol. Chem. 2010, 8, 793, WO2010/131025 and WO2010/122578). Later on (R)-enantiomer has been obtained stereo specifically via asymmetric homogeneous hydrogenation of an enamine precursor using various chiral Rh-catalysts (J. Am. Chem. Soc. 2009, 131, 8796, ibid. 2009, 131, 11316, Org. Proc. Res. Dev. 2006, 10, 723, ibid. 2005, 9, 634, Proc. Chem. Pharm. Ind. 2008, 333 and Tetrahedron Asymmetry 2006, 17, 205 and WO2010/078440). In another approach an enamine precursor containing on nitrogen alkyl substituent as a chiral auxiliary e.g. phenethylamine has been diastereo selectively hydrogenated (Bioorg. Med. Chem. Lett. 2007, 17, 3373, J. Am. Chem. Soc. 2004, 126, 3048 and J. Chem. Res. 2010, 230). Also biocatalytic asymmetric synthesis using transaminase and β-keto acid as the starting material has been published (Science 2010, 329, 305). Further approach via β-hydroxy acid and β-lactam has been reported in J. Org. Chem. 2005, 70, 1949.
No synthesis of Sitagliptin has ever been reported using a chiral starting material from a chiral pool: Recently X. Pan et al. (J. Chem. Res. 2010, 517) realized that configuration of (R)-β-amino acid of formula IIa corresponds the configuration of inexpensive natural L-aspartic acid which could be used as a starting material. Thus, instead of forming the chiral center by expensive stereoselective method, the chiral center of L-aspartic acid has been successfully used first time to generate the chiral center in the (R)-β-amino acid of formula IIa. Nevertheless, the disclosed process as reported by Pan suffers with many drawbacks. Too many steps are necessary just to form an appropriate intermediate of L-aspartic acid which has been then successfully reacted with aromatic Grignard reagent derived from 1,2,4-trifluorobenzene. Although in this concept inexpensive starting material, L-aspartic acid is used, still too many steps are involved and consequently further improvements are required. For a cost efficient manufacture of Sitagliptin there is a clear need for a new process in which either inexpensive L- or racemic aspartic acid would be used as a starting material.